The primary goals of this revised project are; 1) to study the etiology of trisomy 21 including the mechanisms of disfunction and the factor that influence its frequency, and 2) to investigate the phenotypic consequences of the extra chromosome 21. We will use cytogenetic, molecular and epidemiological tools to investigate specific hypotheses generated from our previous work on Down syndrome (DS). These include hypotheses to explain the two established correlates of nondisjunction, advanced maternal age and aberrant levels of recombination, as well as hypotheses concerning environmental exposures. Additionally, we will examine a chromosome 21 gene-speficic dosage model to explain the phenotypic variation seen among DS individuals. Our innovative approach is similar to the strategy used to genetically map disease genes based on affected relative pairs. All studies will take advantage of our well-established resource of DNA results on over 1000 DS individuals and their parents, our Atlanta population epidemiology DS study, our on-going collaborations with the Denmark and California population based DS studies, and our strong team of investigators who have a long-term commitment to understanding the tillage of trisomy 21 and its consequences. The results from this project will provide essential data to elucidate mechanisms of nondisjunction and factors and influence its frequency and will be directly applicable to related studies in Projects II and III. Moreover, mechanisms responsible for maternal age effect will be identified and may point to new strategies of clinical intervention, possibly changing from prevention to preconception therapy. In addition, this will be the first study to provide direct evidence for a specific model to explain the effect of an extra chromosome 21. Identification of susceptibility genes may be used to predict phenotypic outcomes and may lead to possible treatments. Our analytical model to investigate mechanisms of chromosomal disease due to increased gene dosage will be complementary to the genome- based approach to study the pathogenesis of X chromosome abnormalities, as proposed in Project IV. Furthermore, the identification of genes involved in developmental processes or leukemia pathways may be applicable to other disorders found among chromosomally normal individuals.